DESCRIPTION (Adapted from applicants abstract): By means of gene targeting into the immunoglobulin locus of the mouse germ line, a solution of three longstanding problems in B lymphocyte differentiation is attempted: the mechanism of allelic exclusion of immunoglobulin genes, the generation of the antibody repertoire, and the function on immunoglobulin D (IgD). These themes are central to autoimmunity. Most of the immunoglobulin locus of the mouse has been cloned and sequenced. DNA constructs to delete or replace segments of the immunoglobulin locus will be introduced into an embryonic stem cell line. From the transfected line, cells with the appropriate mutation will be cloned and injected into mouse blastocysts, and the resulting mosaic mice will be bred further to yield progeny with the targeted mutation. The targeted mutations include destruction of the gene segment encoding the constant region of immunoglobulin mu chain (Cmu) and delta chain (Cgamma); deletion of a region containing a transcription termination site in the intron between Cmu and Cdelta; and replacement of a DNA fragment by an immunoglobulin gene segment that appears later in B cell ontogeny, specifically, replacement of the embryonic J locus by an already arranged VDJ segment, which encodes the variable region of the immunoglobulin heavy chain. Mice that are homozygous or heterozygous for the mutations will be analyzed by standard immunological and biochemical techniques. Mice lacking functional Cmu will be used to determine the efficiency of generating genes at the immunoglobulin heavy chain locus and thereby, to distinguish between various mechanisms of allelic exclusion. Mice with the deletion of Cdelta or the transcription termination site may reveal the function of IgD, and mice with an already arranged VDJ segment in the germ line will be tested for their antibody repertoire.